Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation.

The inverse effects of creatine supplementation and sleep deprivation on high energy phosphates, neural creatine, and cognitive performances suggest that creatine is a suitable candidate for reducing the negative effects of sleep deprivation. With this, the main obstacle is the limited exogenous uptake by the central nervous system (CNS), making creatine only effective over a long-term diet of weeks. Thus far, only repeated dosing of creatine over weeks has been studied, yielding detectable changes in CNS levels. Based on the hypothesis that a high extracellular creatine availability and increased intracellular energy consumption will temporarily increase the central creatine uptake, subjects were orally administered a high single dose of creatinemonohydrate (0.35 g/kg) while performing cognitive tests during sleep deprivation. Two consecutive 31P-MRS scans, 1H-MRS, and cognitive tests were performed each at evening baseline, 3, 5.5, and 7.5 h after single dose creatine (0.35 g/kg) or placebo during sub-total 21 h sleep deprivation (SD). Our results show that creatine induces changes in PCr/Pi, ATP, tCr/tNAA, prevents a drop in pH level, and improves cognitive performance and processing speed. These outcomes suggest that a high single dose of creatine can partially reverse metabolic alterations and fatigue-related cognitive deterioration.

Neural Correlates of Oral Stereognosis-An fMRI Study.

Oral stereognosis is the ability to recognize, discriminate and localize a bolus in the oral cavity. Clinical observation indicates deficits in oral stereognosis in patients with vascular or neurodegenerative diseases particularly affecting the parietal lobes. However, the precise neural representation of oral stereognosis remains unclear whereas the neural network of manual stereognosis has already been identified. We hypothesize that oral and manual stereognosis share common neuronal substrates whilst also showing somatotopic distribution. Functional magnetic resonance images (fMRI; Siemens Prisma 3 T) from 20 healthy right-handed participants (11 female; mean age 25.7 years) using a cross-modal task of oral and manual spatial object manipulation were acquired. Data were analyzed using FSL software using a block design and standard analytical and statistical procedures. A conjunction analysis targeted the common neuronal substrate for stereognosis. Activations associated with manual and oral stereognosis were found in partially overlapping fronto-parietal networks in a somatotopic fashion, where oral stereognosis is located caudally from manual stereognosis. A significant overlap was seen in the left anterior intraparietal sulcus. Additionally, cerebellar activations were shown particularly for the oral condition. Spatial arrangement of shaped boli in the oral cavity is associated with neuronal activity in fronto-parietal networks and the cerebellum. These findings have significant implications for clinical diagnostics and management of patients with lesions or atrophy in parietal lobule (e.g. Alzheimer's disease, stroke). More studies are required to investigate the clinical effect of damage to these areas, such as loss of oral stereognosis or an impaired oral phase.

Anthropomorphic or non-anthropomorphic? Effects of biological sex in observation of actions in a digital human model and a gantry robot model.

Robots are ever more relevant for everyday life, such as healthcare or rehabilitation, as well as for modern industrial environment. One important issue in this context is the way we perceive robots and their actions. From our previous study, evidence exists that sex can affect the way people perceive certain robot's actions. In our fMRI study, we analyzed brain activations of female and male participants, while they observed anthropomorphic and robotic movements performed by a human or a robot model. While lying in the scanner, participants rated the perceived level of anthropomorphic and robotic likeness of movements in the two models. The observation of the human model and the anthropomorphic movements similarly activated the biological motion coding areas in posterior temporal and parietal areas. The observation of the robot model activated predominantly areas of the ventral stream, whereas the observation of robotic movements activated predominantly the primary and higher order motor areas. To note, this later activation originated mainly from female participants, whereas male participants activated, in both robot model and robotic movements contrasts, areas in the posterior parietal cortex. Accordingly, the general contrast of sex suggests that men tend to use the ventro-dorsal stream most plausibly to rely on available previous knowledge to analyze the movements, whereas female participants use the dorso-dorsal and the ventral streams to analyze online the differences between the movement types and between the different models. The study is a first step toward the understanding of sex differences in the processing of anthropomorphic and robotic movements.

Two Steps to Bicyclo[4.2.0]octadienes from Cyclooctatetraene: Total Synthesis of Kingianic Acid A.

Synthetic approaches to bicyclo[4.2.0]octadiene natural products frequently employ the synthesis of linear tetraenes to initiate a biosynthetic 8π/6π-electrocyclization cascade. This work forges a functionalized bicyclo[4.2.0]octadiene in two steps from cyclooctatetraene. The versatility of this method is demonstrated through natural product synthesis, including the first total synthesis of kingianic acid A and formal syntheses of kingianins A, D, and F and cryptobeilic acid D ethyl ester. The unexpected formation of an E,E,Z,E-tetraene byproduct is rationalized through density functional theory modeling.

Guest-Dependent Isomer Convergence of a Permanently Fluxional Coordination Cage.

A fluxional bis-monodentate ligand, based on the archetypal shape-shifting molecule bullvalene, self-assembles with M2+ (M=Pd2+ or Pt2+ ) to produce a highly complex ensemble of permanently fluxional coordination cages. Metal-mediated self-assembly selects for an M2 L4 architecture while maintaining shape-shifting ligand complexity. A second level of simplification is achieved with guest-exchange; the binding of halides within the M2 L4 cage mixture results in a convergence to a cage species with all four ligands present as the "B isomer". Within this confine, the reaction graph of the bullvalene is greatly restricted, but gives rise to a mixture of 38 possible diastereoisomers in rapid exchange. X-ray crystallography reveals a preference for an achiral form consisting of both ligand enantiomers. Through a combination of NMR spectroscopy and DFT calculations, we elucidate the restricted isomerisation pathway of the permanently fluxional M2 L4 assembly.

Ambimodal Pericyclic Rearrangements of Dialkenyl-Bullvalenes Give Tetrahydro-1,8-ethenoheptalenes.

The fluxional structure of bullvalene is expanded by the discovery of a [5,5]-sigmatropic rearrangement of dialkenyl substituted derivatives. This gives rise to tetrahydro-1,8-ethenoheptalenes (THEH), representing the first examples of this tricyclic scaffold. Variation of the substitution pattern alters the product distribution, including one thermodynamically balanced between THEH and bullvalene isomers. DFT calculations are used to explore the thermodynamic landscape and reaction mechanism revealing a pretransition state bifurcation leading to a concerted ambimodal rearrangement pathway.

Usability and Perceived Usefulness of the AFib 2gether Mobile App in a Clinical Setting: Single-Arm Intervention Study.

BACKGROUND: Although the American Heart Association and other professional societies have recommended shared decision-making as a way for patients with atrial fibrillation (AF) or atrial flutter to make informed decisions about using anticoagulation (AC), the best method for facilitating shared decision-making remains uncertain. OBJECTIVE: The aim of this study is to assess the AFib 2gether mobile app for usability, perceived usefulness, and the extent and nature of shared decision-making that occurred for clinical encounters between patients with AF and their cardiology providers in which the app was used. METHODS: We identified patients visiting a cardiology provider between October 2019 and May 2020. We measured usability from patients and providers using the Mobile App Rating Scale. From the 8 items of the Mobile App Rating Scale, we reported the average score (out of 5) for domains of functionality, esthetics, and overall quality. We administered a 3-item questionnaire to patients relating to their perceived usefulness of the app and a separate 3-item questionnaire to providers to measure their perceived usefulness of the app. We performed a chart review to track the occurrence of AC within 6 months of the index visit. We also audio recorded a subset of the encounters to identify evidence of shared decision-making. RESULTS: We facilitated shared decision-making visits for 37 patients visiting 13 providers. In terms of usability, patients' average ratings of functionality, esthetics, and overall quality were 4.51 (SD 0.61), 4.26 (SD 0.51), and 4.24 (SD 0.89), respectively. In terms of usefulness, 41% (15/37) of patients agreed that the app improved their knowledge regarding AC, and 62% (23/37) agreed that the app helped clarify to their provider their preferences regarding AC. Among providers, 79% (27/34) agreed that the app helped clarify their patients' preferences, 82% (28/34) agreed that the app saved them time, and 59% (20/34) agreed that the app helped their patients make decisions about AC. In addition, 32% (12/37) of patients started AC after their shared decision-making visits. We audio recorded 25 encounters. Of these, 84% (21/25) included the mention of AC for AF, 44% (11/25) included the discussion of multiple options for AC, 72% (18/25) included a provider recommendation for AC, and 48% (12/25) included the evidence of patient involvement in the discussion. CONCLUSIONS: Patients and providers rated the app with high usability and perceived usefulness. Moreover, one-third of the patients began AC, and approximately 50% (12/25) of the encounters showed evidence of patient involvement in decision-making. In the future, we plan to study the effect of the app on a larger sample and with a controlled study design. TRIAL REGISTRATION: ClinicalTrials.gov NCT04118270; https://clinicaltrials.gov/ct2/show/NCT04118270. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-21986.

An optimal antitumor response by a novel CEA/CD3 bispecific antibody for colorectal cancers.

BACKGROUND: CD3-based bispecific T cell engagers (bsTCEs) are one of the most promising bispecific antibodies for effective cancer treatments. To elicit target-specific T cell-mediated cytotoxicity, these bsTCEs contain at least one binding unit directed against a tumor antigen and another binding unit targeting CD3 in T cell receptor complex. Development of CD3-based bsTCEs, however, has been severely hampered by dose-limiting toxicities due to cytokine release syndrome. To address this limitation, we developed a novel functionally trivalent T cell engager (t-TCE) antibody containing affinity-reduced CD3 binding unit positioned to ensure monovalent CD3 engagement, in combination with bivalent tumor antigen binding of carcinoembryonic antigen (CEA). METHODS: We modeled the variable region of anti-CD3 in the complementarity-determining regions of the heavy chain and obtained CD3 binders with reduced binding affinity. Two optimized versions CEA/CD3-v1 and CEA/CD3-v2 were identified and generated in tetravalent format, characterized and compared in vitro and in vivo for functional activity. RESULTS: Our lead candidate, CEA/CD3-v2, demonstrated subnanomolar binding and picomolar potency against a panel of CEA-expressing cancer cell lines. In addition, we detected reduced T cell cytokine release with potent cytotoxic activity. Our t-TCE CEA/CD3-v2 molecule demonstrated strong antitumor effect in a dose-dependent manner in human peripheral blood mononuclear cell (PBMC) xenograft model. Furthermore, combination of CEA/CD3-v2 with atezolizumab provided synergistic antitumor effect. CONCLUSIONS: Because of its effective tumor cell killing in vitro and in vivo with reduced cytokine release, CEA/CD3 bsTCE may greatly benefit in CEA-positive cancer immunotherapy.

A Preliminary Study of Quantitative Ultrasound for Cancer-Risk Assessment of Thyroid Nodules.

Background: Gray-scale, B-mode ultrasound (US) imaging is part of the standard clinical procedure for evaluating thyroid nodules (TNs). It is limited by its instrument- and operator-dependence and inter-observer variability. In addition, the accepted high-risk B-mode US TN features are more specific for detecting classic papillary thyroid cancer rather than the follicular variant of papillary thyroid cancer or follicular thyroid cancer. Quantitative ultrasound (QUS) is a technique that can non-invasively assess properties of tissue microarchitecture by exploiting information contained in raw ultrasonic radiofrequency (RF) echo signals that is discarded in conventional B-mode imaging. QUS provides quantitative parameter-value estimates that are a function of the properties of US scatterers and microarchitecture of the tissue. The purpose of this preliminary study was to assess the performance of QUS parameters in evaluating benign and malignant thyroid nodules. Methods: Patients from the Thyroid Health Center at the Boston Medical Center were recruited to participate. B-mode and RF data were acquired and analyzed in 225 TNs (24 malignant and 201 benign) from 208 patients. These data were acquired either before (167 nodules) or after (58 nodules) subjects underwent fine-needle biopsy (FNB). The performance of a combination of QUS parameters (CQP) was assessed and compared with the performance of B-mode risk-stratification systems. Results: CQP produced an ROC AUC value of 0.857 ± 0.033 compared to a value of 0.887 ± 0.033 (p=0.327) for the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) and 0.880 ± 0.041 (p=0.367) for the American Thyroid Association (ATA) risk-stratification system. Furthermore, using a CQP threshold of 0.263 would further reduce the number of unnecessary FNBs in 44% of TNs without missing any malignant TNs. When CQP used in combination with ACR TI-RADS, a potential additional reduction of 49 to 66% in unnecessary FNBs was demonstrated. Conclusion: This preliminary study suggests that QUS may provide a method to classify TNs when used by itself or when combined with a conventional gray-scale US risk-stratification system and can potentially reduce the need to biopsy TNs.

Stereomutation of Substituted Bullvalenes.

The stereomutation of substituted bullvalenes is an inevitable consequence of the valence isomerism that automerizes this unique fluxional hydrocarbon. The introduction of external stereogenicity in the substituents expands the reaction graphs and leads to a wealth of complex diastereochemical relationships. In this communication, we explore these possibilities and prepare a range of stereochemically rich substituted bullvalenes. This includes a series of disubstituted bullvalenes with two external stereocenters as a platform for fluxional, shape-diverse compound libraries. We also prepare a tethered bisbullvalene with central stereogenicity in the tether as an ensemble of 900 unique isomers that are completely stereomutable.

Gender Effects in Observation of Robotic and Humanoid Actions.

Robots are gaining an increasingly important role in industrial production. Notably, a high level of acceptance is an important factor for co-working situation between human and robot. The aim of the present study was to investigate the differences in the perception of anthropomorphic and robotic movements using models consisting of a virtual robot and a digital human. Videos of each model displayed different degrees of human likeness or robot likeness in speed and trajectories of placing movements. Female and male participants were asked to rate on a Likert scale the perceived levels of human likeness or robot likeness in the two models. Overall, results suggest that males were sensitive to the differences between robotic and anthropomorphic movements, whereas females showed no difference between them. However, compared to males, female participants attributed more anthropomorphic features to robotic movements. The study is a first step toward a more comprehensive understanding of the human ability to differentiate between anthropomorphic and robotic movements and suggests a crucial role of gender in the human-robot interaction.

Boronate Ester Bullvalenes.

Boronate ester bullvalenes are now accessible in two to four operationally simple steps. This unlocks late-stage diversification through Suzuki cross-coupling reactions to give mono-, di-, and trisubstituted bullvalenes. Moreover, a linchpin strategy enables preprogrammed installation of two different substituents. Analysis of solution phase isomer distributions and single-crystal X-ray structures reveals that isomer preference in the crystal lattice is due to general shape selectivity.

Diffusion Tensor Imaging Reveals Microstructural Heterogeneity of Normal-Appearing White Matter and Related Cognitive Dysfunction in Glioma Patients.

Immunohistochemical data based on isocitrate-dehydrogenase (IDH) mutation status have redefined glioma as a whole-brain disease, while occult tumor cell invasion along white matter fibers is inapparent in conventional magnetic resonance imaging (MRI). The functional and prognostic impact of focal glioma may however relate to the extent of white matter involvement. We used diffusion tensor imaging (DTI) to investigate microstructural characteristics of whole-brain normal-appearing white matter (NAWM) in relation to cognitive functions as potential surrogates for occult white matter involvement in glioma. Twenty patients (12 IDH-mutated) and 20 individually matched controls were preoperatively examined using DTI combined with a standardized neuropsychological examination. Tumor lesions including perifocal edema were masked, and fractional anisotropy (FA) as well as mean, radial, and axial diffusivity (MD, RD, and AD, respectively) of the remaining whole-brain NAWM were determined by using Tract-Based Spatial Statistics and histogram analyses. The relationship between extratumoral white matter integrity and cognitive performance was examined using partial correlation analyses controlling for age, education, and lesion volumes. In patients, mean FA and AD were decreased as compared to controls, which agrees with the notion of microstructural impairment of NAWM in glioma patients. Patients performed worse in all cognitive domains tested, and higher anisotropy and lower MD and RD values of NAWM were associated with better cognitive performance. In additional analyses, IDH-mutated and IDH-wildtype patients were compared. Patients with IDH-mutation showed higher FA, but lower MD, AD, and RD values as compared to IDH-wildtype patients, suggesting a better preserved microstructural integrity of NAWM, which may relate to a less infiltrative nature of IDH-mutated gliomas. Diffusion-based phenotyping and monitoring microstructural integrity of extratumoral whole-brain NAWM may aid in estimating occult white matter involvement and should be considered as a complementary biomarker in glioma.

Strategies of selective changing: Preparatory neural processes seem to be responsible for differences in complex inhibition.

Selective inhibition describes the stopping of an action while other actions are further executed. It can be differentiated between two strategies to stop selectively: the fast but global stop all, then discriminate strategy and the slower but more selective first discriminate, then stop strategy. It is assumed that the first discriminate, then stop strategy is especially used when information regarding which action might have to be stopped is already available beforehand. Moreover, it is supposed that both strategies differ in matters of basal ganglia pathways used for their execution. Aim of the present study was to investigate the use of the two strategies in situations requiring selective changing of an action. Eighteen healthy male participants performed a selective stop-change task with informative and uninformative cues during fMRI. Behavioral results show that informative cues led to a benefit in both inhibition times and selectivity. FMRI data revealed that the same cortico-subcortical pathway was used with informative and uninformative cues. Behavioral and neuronal results indicate that participants used the first discriminate, then stop strategy for selective inhibition irrespective of the amount of previously available information. Moreover, the neural activity data indicate that the benefit in the informed condition was produced by an efficient preparation for the concrete change process. Possible factors that might affect which strategy is used for selective stopping are the level of previously available information (foreknowledge) and the experimental set-up, as e.g. task complexity.

Proton Magnetic Resonance Spectroscopy of the motor cortex reveals long term GABA change following anodal Transcranial Direct Current Stimulation.

Anodal transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has been reported to increase the firing rates of neurons and to modulate the gamma-aminobutyric acid (GABA) concentration. To date, knowledge about the nature and duration of these tDCS induced effects is incomplete. We aimed to investigate long-term effects of anodal tDCS over M1 on GABA dynamics in humans. Repeated magnetic resonance spectroscopy (MRS) was employed to measure relative GABA concentration in M1 for approximately 64 minutes after stimulation. The study was performed on 32 healthy subjects. Either anodal or sham tDCS were applied for 10 minutes with the active electrode over the left M1 and the reference electrode over the right supra-orbital region. Pre and post-tDCS MRS scans were performed to acquire GABA-edited spectra using 3 T Prisma Siemens scanner. GABA signals showed no change over time in the sham tDCS group, whereas anodal tDCS resulted in a significant early decrease within 25 minutes after tDCS and then significant late decrease after 66 minutes which continued until the last test measurements. The late changes in GABA concentration might be related to long-term plasticity mechanism. These results contribute to a better understanding of the neurochemical mechanism underlying long-term cortical plasticity following anodal tDCS.

Impaired Emotional Mirroring in Parkinson's Disease-A Study on Brain Activation during Processing of Facial Expressions.

BACKGROUND: Affective dysfunctions are common in patients with Parkinson's disease, but the underlying neurobiological deviations have rarely been examined. Parkinson's disease is characterized by a loss of dopamine neurons in the substantia nigra resulting in impairment of motor and non-motor basal ganglia-cortical loops. Concerning emotional deficits, some studies provide evidence for altered brain processing in limbic- and lateral-orbitofrontal gating loops. In a second line of evidence, human premotor and inferior parietal homologs of mirror neuron areas were involved in processing and understanding of emotional facial expressions. We examined deviations in brain activation during processing of facial expressions in patients and related these to emotion recognition accuracy. METHODS: 13 patients and 13 healthy controls underwent an emotion recognition task and a functional magnetic resonance imaging (fMRI) measurement. In the Emotion Hexagon test, participants were presented with blends of two emotions and had to indicate which emotion best described the presented picture. Blended pictures with three levels of difficulty were included. During fMRI scanning, participants observed video clips depicting emotional, non-emotional, and neutral facial expressions or were asked to produce these facial expressions themselves. RESULTS: Patients performed slightly worse in the emotion recognition task, but only when judging the most ambiguous facial expressions. Both groups activated inferior frontal and anterior inferior parietal homologs of mirror neuron areas during observation and execution of the emotional facial expressions. During observation, responses in the pars opercularis of the right inferior frontal gyrus, in the bilateral inferior parietal lobule and in the bilateral supplementary motor cortex were decreased in patients. Furthermore, in patients, activation of the right anterior inferior parietal lobule was positively related to accuracy in the emotion recognition task. CONCLUSION: Our data provide evidence for a contribution of human homologs of monkey mirror areas to the emotion recognition deficit in Parkinson's disease.

A comparison of continuous infusion and intermittent bolus administration of 0.1% ropivacaine with 0.0002% fentanyl for epidural labor analgesia.

BACKGROUND AND AIMS: Minimal consumption of local anesthetic and opioid for epidural labor analgesia has been advocated for safe obstetric outcome and superior maternal satisfaction. The primary objective of this study was to evaluate and compare the analgesic efficacy of mode of administration of epidural 0.1% ropivacaine with 0.0002% fentanyl via continuous infusion or intermittent boluses during labor. MATERIAL AND METHODS: Sixty term primi or second gravida healthy parturients in labor requesting epidural analgesia were recruited in this study. Lumbar epidural catheter was inserted, and analgesia initiated with 0.2% ropivacaine. Patients were randomized to receive ropivacaine 0.1% with fentanyl 0.0002% via either continuous infusion (Group A) or intermittent boluses (Group B) on an hourly basis. If the parturient complained of pain and visual analog scale (VAS) score was >3, an additional bolus of the study drug was given. VAS score, motor blockade, maternal hemodynamics and fetal heart sounds were frequently monitored. Side effects, mode of delivery and neonatal outcome were noted. RESULTS: To achieve similar VAS, the mean total dose of ropivacaine was 18.78 ± 3.88 mg in Group A and 16.86 ± 4.3 mg in Group B, the difference being statistically significant (P = 0.04). Seventeen out of 30 patients in Group A that is, 56.6% and nine patients in Group B that is, 30% required additional top-ups, and this was significantly higher (P = 0.037). Side effects, mode of delivery and neonatal outcome were comparable in both groups. CONCLUSION: Intermittent bolus administration provides a more efficacious route of drug delivery when compared to continuous infusion by significantly decreasing the total amount of local anesthetic plus opioid without adversely affecting patient safety or maternal satisfaction.